Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1963860 | Cellular Signalling | 2010 | 10 Pages |
Abstract
Gαq directly activates p63RhoGEF and closely related catalytic domains found in Trio and Kalirin, thereby linking Gq-coupled receptors to the activation of RhoA. Although the crystal structure of Gαq in complex with the catalytic domains of p63RhoGEF is available, the molecular mechanism of activation has not yet been defined. In this study, we show that membrane translocation does not appear to play a role in Gαq-mediated activation of p63RhoGEF, as it does in some other RhoGEFs. Gαq instead must act allosterically. We next identify specific structural elements in the PH domain that inhibit basal nucleotide exchange activity, and provide evidence that Gαq overcomes this inhibition by altering the conformation of the α6-αN linker that joins the DH and PH domains, a region that forms direct contacts with RhoA. We also identify residues in Gαq that are important for the activation of p63RhoGEF and that contribute to Gα subfamily selectivity, including a critical residue in the Gαq C-terminal helix, and demonstrate the importance of these residues for RhoA activation in living cells.
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Biochemistry, Genetics and Molecular Biology
Biochemistry
Authors
Aruna Shankaranarayanan, Cassandra A. Boguth, Susanne Lutz, Christiane Vettel, Franca Uhlemann, Mohamed Aittaleb, Thomas Wieland, John J.G. Tesmer,